This project's general hypothesis is that genetic factors influence individual susceptibility to chronic pancreatitis (CP). Past work from this lab associated idiopathic CP (ICP) with mutations of CFTR, the cystic fibrosis gene. Specifically, 15-20% of Caucasian ICP patients were found to have two CFTR mutations, abnormal nasal CFTR-mediated ion transport, and extra pancreatic findings consistent with reduced CFTR function. This proposal follow s up on these findings by addressing two aims: AIM #1 will test a series of ICP patients for CFTR mutations and for CFTR function. This effort is designed to identify the CFTR genotypes causing highest susceptibility to ICP and to measure how much these genotypes influence ICP risk. Caucasian and African-American ICP patients will be compared wit h controls (without pancreatitis) by comprehensively testing the CFTR gene. CFTR functional testing will then be used to confirm the impact of these genotypes on CFTR-mediated ion transport and to identify patients wit h CFTR-related ICP in whom reduced CFTR function would not have been predicted by DNA testing (e.g., due to polymorphism s or splice variants).Additional studies will test the prediction that the N34S PSTI mutation independently increases ICP risk in individuals with CFTR mutations. AIM 2 will study the role of CFTR in alcoholic CP (ACP). Data from several groups argues against a major role for CFTR in determine in g ACP risk in most cases. Nonetheless, we found an excess of CFTR mutation s in a pilot study of ACP patients who had early-onset disease (p <0.005). We therefore will compare the frequency of CFTR mutation s in patients with early-onset ACP (by age 36, first quartile) versus control subjects. Additional studies will explore the relationship between abnormal CFTR genotypes and CFTR-mediated nasal ion transport in ACP. CP affects over 300,000Americans. This study is expected to clarify the genetic basis for roughly 40,000 of these cases. It also is expected to develop improved CFTR gene testing methods that will identify an additional 160,000asymptomatic individual s who are highly susceptible to developing CP (roughly 200 times normal). Finally, this data will provide a foundation for further studies testing whether CP-associated abnormal CFTR genotypes affect pancreatic ductal secretion in vivo in susceptible individuals who have not yet developed CP. Thus, this project's general goals are to develop methods to identify health y individuals who are highly susceptible to CP and CP, and to work towards developing preventative therapy for these individuals.